Use of cyclosporine analogues for treating fibrosis

Abstract

Disclosed herein include methods, compositions, and kits suitable for use in preventing, treating or reverse fibrosis. The methods comprise administering to a subject in need thereof a composition comprising a cyclosporine analogue (for example, CRV431), or a pharmaceutically acceptable salt, solvate, stereoisomer thereof. The compositions and kits comprise a cyclosporine analogue (for example, CRV431), or a pharmaceutically acceptable salt, solvate, stereoisomer thereof.

What is claimed is: 
     
       1. A method for reducing production of extracellular matrix (ECM) molecules in a subject having fibrosis or at risk of developing fibrosis, the method comprising: selecting a composition to reduce the production of the ECM molecules in the subject, the composition comprising: 
       
         
           
           
               
               
           
         
       
       and contacting at least one fibroblastic cell of the subject with an effective dose of the composition. 
     
     
       2. The method of  claim 1 , wherein the subject is suffering from fibrosis. 
     
     
       3. The method of  claim 1 , comprising inhibiting fibrosis formation in the subject. 
     
     
       4. The method of  claim 1 , wherein the fibrosis is non-liver fibrosis. 
     
     
       5. The method of  claim 1 , wherein the fibrosis is liver fibrosis. 
     
     
       6. The method of  claim 5 , wherein the liver fibrosis is cirrhosis or non-alcoholic steatohepatitis (NASH). 
     
     
       7. The method of  claim 6 , wherein the cirrhosis is associated with viral hepatitis, schistosomiasis and chronic alcoholism. 
     
     
       8. The method of  claim 1 , wherein the fibrosis is induced by a therapeutic agent, an injury, or a combination thereof. 
     
     
       9. The method of  claim 1 , comprising reducing fibrosis formation in the subject by at least 5%, 10%, 20%, 50%, 70%, 90%, or more as compared to untreated subjects. 
     
     
       10. The method of  claim 1 , comprising delaying fibrosis formation in the subject as compared to untreated subjects. 
     
     
       11. The method of  claim 1 , further comprising contacting the fibroblastic cell with one or more additional therapeutic agents. 
     
     
       12. The method of  claim 11 , wherein the one or more additional therapeutic agents comprise an additional antifibrotic agent or an anti-inflammatory agent. 
     
     
       13. The method of  claim 1 , further comprising after the contacting, measuring the expression of one or more biomarker genes selected from the group consisting of: Endothelial Cell Specific Molecule 1 (ESM1), Nuclear Receptor Coactivator 3 (NCOA3), Interferon Induced Protein 44 Like (IFI44L), MicroRNA 194-2 (mIR-194-2), Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1), Lysyl Oxidase Like 2 (LOXL2), Ubiquitin D/Human leukocyte antigen (HLA)-F adjacent transcript 10 (UBD/FAT10), STRA6 Signaling Receptor And Transporter Of Retinol (STRA6), RCC1 Domain Containing 1 (RCCD1), and Dual Oxidase 2 (DUOX2). 
     
     
       14. The method of  claim 1 , further comprising after the contacting, measuring secretion of one or more markers selected from monocyte chemoattractant protein (MCP-1), interleukin-6 (IL-6), matrix metalloproteinase-7 (MMP-7), tissue inhibitor of metalloproteinase-1 (TIMP1), hyaluronic acid, and collagen 1α1. 
     
     
       15. The method of  claim 1 , wherein the effective dose has a dose concentration ranging from 0.2 μM to 5 μM. 
     
     
       16. The method of  claim 1 , wherein the effective dose comprises an effective daily dose of CRV431 at from 10 mg to 250 mg. 
     
     
       17. The method of  claim 1 , wherein the fibroblast cell is selected from the group consisting of lung fibroblasts, cardiac fibroblasts, dermal fibroblasts, renal mesangial cells, and hepatic stellate cells. 
     
     
       18. A method for reducing non-liver fibrosis or reversing non-liver fibrosis in a subject having non-liver fibrosis, the method comprising:
 administering to the subject having non-liver fibrosis a pharmaceutically effective amount of a composition comprising: 
 
       
         
           
           
               
               
           
         
       
       thereby reducing the non-liver fibrosis or reversing the non-liver fibrosis by reducing the production of extracellular matrix molecules. 
     
     
       19. The method of  claim 18 , wherein the non-liver fibrosis is pulmonary fibrosis or scleroderma.